Transdermal delivery formulation

ABSTRACT

The invention provides compositions and methods for delivering vitamin D to a human subject. In one embodiment the invention provides a transdermal patch for the transdermal administration of vitamin D comprising: (a) a backing layer that serves as the outer surface of the patch during use; (b) an adhesive drug reservoir layer for affixing the patch to human skin; and (c) a release liner, which upon removal exposes the adhesive drug reservoir layer. The adhesive drug reservoir layer can include vitamin D, a polymeric adhesive, an organic solvent, and a permeation enhancer.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/736,651 filed Dec. 14, 2017, which is a National Stage filing under35 U.S.C. § 371 of International Application No. PCT/US2016/037437 filedJun. 14, 2016, which claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Patent Application No. 62/175,363, filed Jun. 14, 2015,which applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

The delivery of drugs through the skin provides many advantages;primarily, such a means of delivery is a comfortable, convenient andnoninvasive way of administering drugs. The variable rates of absorptionand metabolism encountered in oral treatment are avoided, and otherinherent inconveniences, e.g., gastrointestinal irritation and the like,are eliminated as well. Transdermal drug delivery also makes possible ahigh degree of control over blood concentrations of any particular drug.

Skin is a structurally complex, relatively thick membrane. Moleculesmoving from the environment into and through intact skin must firstpenetrate the stratum corneum and any material on its surface. They mustthen penetrate the viable epidermis, the papillary dermis, and thecapillary walls into the blood stream or lymph channels. To be soabsorbed, molecules must overcome a different resistance to penetrationin each type of tissue. Transport across the skin membrane is thus acomplex phenomenon. However, it is the cells of the stratum corneum,which present the primary barrier to absorption of topical compositionsor transdermally administered drugs. The stratum corneum is a thin layerof dense, highly keratinized cells approximately 10-15 microns thickover most of the body. It is believed to be the high degree ofkeratinization within these cells as well as their dense packing whichcreates in most cases a substantially impermeable barrier to drugpenetration. With many drugs, the rate of permeation through the skin isextremely low without the use of some means to enhance the permeabilityof the skin.

Numerous chemical agents have been studied as a means of increasing therate at which a drug penetrates through the skin. As will be appreciatedby those in the field, chemical enhancers are compounds that areadministered along with the drug (or in some cases the skin may bepretreated with a chemical enhancer) in order to increase thepermeability of the stratum corneum, and thereby provide for enhancedpenetration of the drug through the skin. Ideally, such chemicalpenetration enhancers or “permeation enhancers,” as the compounds arereferred to herein, are compounds that are innocuous and serve merely tofacilitate diffusion of the drug through the stratum corneum. Thepermeability of many therapeutic agents with diverse physicochemicalcharacteristics may be enhanced using these chemical enhancement means.However, there are skin irritation and sensitization problems associatedwith high levels of certain enhancers.

Accordingly, although there are many chemical methods of enhancingpermeation, there remains an ongoing need for a method that is highlyeffective in increasing the rate at which a drug permeates the skin,does not result in skin damage, irritation, sensitization, or the like,and can be used to effect transdermal delivery of fat-soluble compoundssuch as vitamin D. It has now been discovered that the formulationdescribed herein is highly effective and provides all of theaforementioned advantages relative to known permeation enhancers.

SUMMARY

The invention provides a transdermal patch for the transdermaladministration of vitamin D comprising: (a) a backing layer that servesas the outer surface of the patch during use; (b) an adhesive drugreservoir layer for affixing the patch to human skin; and (c) a releaseliner, which upon removal exposes the adhesive drug reservoir layer. Theadhesive drug reservoir layer can include, or can consist only of,vitamin D, a polymeric adhesive, an organic solvent, and a permeationenhancer.

In one embodiment, the vitamin D is cholecalciferol (vitamin D₃),calcifediol (25-hydroxyvitamin D₃), ergocalciferol (vitamin DAcalcitriol, or calcipotriene. In one embodiment, the adhesive is apolyisobutylene adhesive, a silicone adhesive; or an acrylate adhesive.

In one embodiment, the adhesive drug reservoir layer comprises about1-10 wt. % of the vitamin D. In one embodiment, the adhesive drugreservoir layer comprises about 60-90 wt. % of the polymeric adhesive.In one embodiment, the adhesive drug reservoir layer comprises about1-15 wt. % of the organic solvent. In one embodiment, the adhesive drugreservoir layer comprises about 1-15 wt. % of the permeation enhancer.In one specific embodiment, the vitamin D is cholecalciferol, theadhesive is an acrylate adhesive, the organic solvent is ethanol, andthe permeation enhancer is transcutol. In other specific embodiments,the organic solvent is isosorbide dimethyl ether, isopropyl laurate, ormethyl laurate.

In some embodiments, the adhesive drug reservoir layer does not containwater. In various embodiments, the adhesive drug reservoir layer doesnot contain an organic base or an inorganic base.

In certain embodiments, the surface area of the adhesive drug reservoirlayer of the patch is about 30 cm² to about 50 cm². In variousembodiments, the patch is formulated to deliver greater than 2,000 μg ofvitamin D through 40 cm² of intact unbroken living skin in within 5hours. In some embodiments, the patch is formulated to deliver greaterthan 20,000 μg of vitamin D through 40 cm² of intact unbroken livingskin in within 24 hours. In some embodiments, the patch is formulated tocontain about 2,000 to about 300,000 I.U. of vitamin D. In otherembodiments, the patch is formulated to contain about 4,000 to about50,000 I.U. of vitamin D. In certain embodiments, the patch isformulated to contain about 4,000 to about 10,000 I.U. of vitamin D. Incertain other embodiments, the patch is formulated to contain about4,000 to about 5,000 I.U. of vitamin D. In one embodiments, the patch isformulated to contain about 4,000 I.U. of vitamin D.

The invention also provides a transdermal patch for the transdermaladministration of vitamin D₃ consisting of: (a) a backing layer thatserves as the outer surface of the patch during use; (b) an adhesivedrug reservoir layer for affixing the patch to human skin; and (c) arelease liner, which upon removal exposes the adhesive drug reservoirlayer; wherein the adhesive drug reservoir layer consists of 1-10 wt. %of vitamin D₃, 60-90 wt. % of a polymeric adhesive, an organic solvent,and 1-15 wt. % of transcutol. The adhesive drug reservoir layer canconsist of about 3 wt. % of vitamin D₃, 80-85 wt. % of a polymericadhesive, an organic solvent, and 5-10 wt. % of transcutol.

The invention further provides a method for the transdermal delivery ofvitamin D comprising removing the release liner of a transdermal patchdescribed herein and applying the transdermal patch to intact unbrokenliving skin of a human subject, wherein the transdermal patch deliversgreater than 0.75 μg/cm² of vitamin D to the subject within 5 hours, orat least 10 μg/cm² of vitamin D to the subject within 48 hours (seeFIGS. 3 and 4 ).

The transdermal patch can be applied to a subject having a25-hydroxyvitamin D₃ blood serum level of less than 30 ng/mL. Thetransdermal patch can be applied to a subject having a 25-hydroxyvitaminD₃ blood serum level of about 1 ng/mL to about 25 ng/mL. In someembodiments, the 25-hydroxyvitamin D₃ blood serum level of the subjectincreases to greater than 30 ng/mL within 5 hours. In variousembodiments, the transdermal patch is applied to the subject once perday for at least 5 days. In one specific embodiment, the human subjecthas a 25-hydroxyvitamin D₃ blood serum level of less than 20 ng/mL. Inanother specific embodiment, the human subject has cystic fibrosis, isolder than 65 years of age, has undergone bariatric surgery, or acombination thereof.

The invention also provides a method of increasing the 25-hydroxyvitaminD₃ blood serum level of a human subject that has a vitamin Dmalabsorption condition comprising removing the release liner of thetransdermal patch described herein and applying the transdermal patch tointact unbroken living skin of the human subject, wherein the25-hydroxyvitamin D₃ blood serum level of the subject increases togreater than 20 ng/mL within 24 hours. The human subject that can have avitamin D malabsorption condition is a subject that has been diagnosedwith cystic fibrosis.

The invention therefore provides for the use of the compositionsdescribed herein for use in medical therapy. The medical therapy can betreating cystic fibrosis and symptoms associated therewith. Theinvention also provides for the use of a composition as described hereinfor the manufacture of a medicament to treat an adverse health conditionin a mammal, for example, a vitamin D deficiency in a human. Themedicament can include a pharmaceutically acceptable diluent, excipient,or carrier, and can be delivered by an occlusive transdermal patch.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the specification and are includedto further demonstrate certain embodiments or various aspects of theinvention. In some instances, embodiments of the invention can be bestunderstood by referring to the accompanying drawings in combination withthe detailed description presented herein. The description andaccompanying drawings may highlight a certain specific example, or acertain aspect of the invention. However, one skilled in the art willunderstand that portions of the example or aspect may be used incombination with other examples or aspects of the invention.

FIG. 1 . Summary graph of cholecalciferol permeation from formulationswithout adhesives showing data collected from 5 hours to 36 hourspost-application.

FIG. 2 . Summary table of cholecalciferol permeation from formulationswithout adhesives showing data collected at 5 hours post-application.

FIG. 3 . Graph of cholecalciferol permeation from formulations withadhesive and isosorbide dimethyl ether as an organic solvent/vitamin Dsolubilizer; average results, n=3.

FIG. 4 . Graph of cholecalciferol permeation from formulations withadhesive and isopropyl laurate as an organic solvent/vitamin Dsolubilizer; average results, n=3.

FIG. 5 . Graph of cholecalciferol permeation from the commercialproducts Respro Laboratories Vitamin D Patch (280,000 I.U.), Patch MDVitamin D3 Topical Patch (5,000 I.U.), and Living Nutritionals VitaminD3 Sunshine Patch (5,000 I.U.), showing that none of the threecommercial patches delivered vitamin D transdermally via Franz Cellevaluations. The data points of all three sets of samples reside on thebaseline.

DETAILED DESCRIPTION

The compositions and methods described herein can involves the use of adrug delivery system, e.g., a topical or transdermal “patch,” whereinthe active agent is contained within a laminated structure that is to beaffixed to the skin. In such a structure, the drug composition iscontained in a layer, or “reservoir,” underlying an upper backing layerthat serves as the outer surface of the device during use. The laminatedstructure may contain a single reservoir, or it may contain multiplereservoirs.

Accordingly, another embodiment of the invention is a system for theenhanced topical or transdermal administration of a drug, comprising:(a) at least one drug reservoir containing the drug and apharmaceutically acceptable carrier; (b) a means for maintaining thesystem in drug and base transmitting relationship to the body surfaceand forming a body surface-system interface; and (c) a backing layerthat serves as the outer surface of the device during use.

In one embodiment, the drug reservoir comprises a polymeric matrix of apharmaceutically acceptable adhesive material that serves to affix thesystem to the skin during drug delivery; typically, the adhesivematerial is a pressure-sensitive adhesive (PSA) that is suitable forlong-term skin contact, and which should be physically and chemicallycompatible with the active agent, inorganic or organic base, and anycarriers, vehicles or other additives that are present. Examples ofsuitable adhesive materials include, but are not limited to, thefollowing: polyethylenes; polysiloxanes; polyisobutylenes;polyacrylates; polyacrylamides; polyurethanes; plasticizedethylene-vinyl acetate copolymers; and tacky rubbers such aspolyisobutene, polybutadiene, polystyrene-isoprene copolymers,polystyrene-butadiene copolymers, and neoprene (polychloroprene). Onespecific adhesive is polyisobutylene.

The backing layer functions as the primary structural element of thetransdermal system and provides the device with flexibility and,preferably, occlusivity. The material used for the backing layer shouldbe inert and incapable of absorbing the drug, the base enhancer, orother components of the formulation contained within the device. Thebacking is preferably comprised of a flexible elastomeric material thatserves as a protective covering to prevent loss of drug and/or vehiclevia transmission through the upper surface of the patch, and willpreferably impart a degree of occlusivity to the system, such that thearea of the body surface covered by the patch becomes hydrated duringuse. The material used for the backing layer should permit the device tofollow the contours of the skin and be worn comfortably on areas of skinsuch as at joints or other points of flexure, that are normallysubjected to mechanical strain with little or no likelihood of thedevice disengaging from the skin due to differences in the flexibilityor resiliency of the skin and the device. The materials used as thebacking layer are either occlusive or permeable, as noted above,although occlusive backings are preferred, and are generally derivedfrom synthetic polymers (e.g., polyester, polyethylene, polypropylene,polyurethane, polyvinylidine chloride, and polyether amide), naturalpolymers (e.g., cellulosic materials), or macroporous woven and nonwovenmaterials.

During storage and prior to use, the laminated structure preferablyincludes a release liner. Immediately prior to use, this layer isremoved from the device so that the system may be affixed to the skin.The release liner should be made from a drug/vehicle impermeablematerial, and is a disposable element, which serves only to protect thedevice prior to application. Typically, the release liner is formed froma material impermeable to the pharmacologically active agent and thebase enhancer, and is easily stripped from the transdermal patch priorto use.

In an alternative embodiment, the drug-containing reservoir and skincontact adhesive are present as separate and distinct layers, with theadhesive underlying the reservoir. In such a case, the reservoir may bea polymeric matrix as described above. Alternatively, the reservoir maybe comprised of a liquid or semisolid formulation contained in a closedcompartment or pouch, or it may be a hydrogel reservoir, or may takesome other form. Hydrogel reservoirs are particularly preferred herein.As will be appreciated by those skilled in the art, hydrogels aremacromolecular networks that absorb water and thus swell but do notdissolve in water. That is, hydrogels contain hydrophilic functionalgroups that provide for water absorption, but the hydrogels arecomprised of crosslinked polymers that give rise to aqueousinsolubility. Generally, then, hydrogels are comprised of crosslinkedhydrophilic polymers such as a polyurethane, a polyvinyl alcohol, apolyacrylic acid, a polyoxyethylene, a polyvinylpyrrolidone, apoly(hydroxyethyl methacrylate) (poly(HEMA)), or a copolymer or mixturethereof. Particularly preferred hydrophilic polymers are copolymers ofHEMA and polyvinylpyrrolidone.

Additional layers, e.g., intermediate fabric layers and/orrate-controlling membranes, may also be present in any of these drugdelivery systems. Fabric layers may be used to facilitate fabrication ofthe device, while a rate-controlling membrane may be used to control therate at which a component permeates out of the device. The component maybe a drug, a base enhancer, an additional enhancer, or some othercomponent contained in the drug delivery system.

A rate-controlling membrane, if present, will be included in the systemon the skin side of one or more of the drug reservoirs. The materialused to form such a membrane is selected so as to limit the flux of oneor more components contained in the drug formulation. Representativematerials useful for forming rate-controlling membranes includepolyolefins such as polyethylene and polypropylene, polyamides,polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetatecopolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinylethylacetate copolymer, ethylene-vinyl propylacetate copolymer,polyisoprene, polyacrylonitrile, ethylene-propylene copolymer, and thelike.

Generally, the underlying surface of the transdermal device, i.e., theskin contact area, has an area in the range of about 5-200 cm²,preferably 5-100 cm², more preferably 20-60 cm². That area will vary, ofcourse, with the amount of drug to be delivered and the flux of the drugthrough the body surface. Larger patches can be used to accommodatelarger quantities of drug, while smaller patches can be used for smallerquantities of drug and/or drugs that exhibit a relatively highpermeation rate.

Such drug delivery systems may be fabricated using conventional coatingand laminating techniques known in the art. For example, adhesive matrixsystems can be prepared by casting a fluid admixture of adhesive, drugand vehicle onto the backing layer, followed by lamination of therelease liner. Similarly, the adhesive mixture may be cast onto therelease liner, followed by lamination of the backing layer.Alternatively, the drug reservoir may be prepared in the absence of drugor excipient, and then loaded by soaking in a drug/vehicle mixture. Ingeneral, transdermal systems of the invention are fabricated by solventevaporation, film casting, melt extrusion, thin film lamination, diecutting, or the like. The inorganic or organic base permeation enhancerwill generally be incorporated into the device during patch manufacturerather than subsequent to preparation of the device. Thus, for acidaddition salts of basic drugs (e.g., hydrochloride salts of aminedrugs), the enhancer will neutralize the drug during manufacture of thedrug delivery system, resulting in a final drug delivery system in whichthe drug is present in nonionized, neutral form along with an excess ofbase to serve as a permeation enhancer. For nonionized acidic drugs, thebase will neutralize such drugs by converting them to the ionized drugin salt form.

In a preferred delivery system, an adhesive overlayer that also servesas a backing for the delivery system is used to better secure the patchto the body surface. This overlayer is sized such that it extends beyondthe drug reservoir so that adhesive on the overlayer comes into contactwith the body surface. The overlayer is useful because the adhesive/drugreservoir layer may lose its adhesion a few hours after application dueto hydration. By incorporating an adhesive overlayer, the deliverysystem will remain in place for the required period of time.

Other types and configurations of transdermal drug delivery systems mayalso be used in conjunction with the method of the present invention, aswill be appreciated by those skilled in the art of transdermal drugdelivery. See, for example, Ghosh, Transdermal and Topical Drug DeliverySystems (Interpharm Press, 1997), particularly Chapters 2 and 8.

As with the topically applied formulations of the invention, the drugand enhancer composition contained within the drug reservoir(s) of theselaminated systems may comprise a number of additional components. Insome cases, the drug and enhancer may be delivered neat, i.e., in theabsence of additional liquid. In most cases, however, the drug will bedissolved, dispersed or suspended in a suitable pharmaceuticallyacceptable vehicle, typically a solvent or gel. Other components thatmay be present include preservatives, stabilizers, surfactants,solubilizers, additional enhancers, and the like.

The invention accordingly provides a novel and highly effective meansfor increasing the flux of an active agent through the body surface(skin or mucosal tissue) of a human or animal. The base enhancersdiscussed herein, employed in specific amounts relative to a formulationor drug reservoir, may be used as permeation enhancers with a widevariety of drugs and drug types, including free acids, free bases, acidaddition salts of basic drugs, basic addition salts of acidic drugs,nonionizable drugs, peptides and proteins. Surprisingly, the increase inpermeation is not accompanied by any noticeable tissue damage,irritation, or sensitization. The invention thus represents an importantadvance in the field of drug delivery.

It is to be understood that while the invention has been described inconjunction with the preferred specific embodiments thereof, theforegoing description is intended to illustrate and not limit the scopeof the invention. Other aspects, advantages and modifications will beapparent to those skilled in the art to which the invention pertains.Furthermore, the practice of the present invention will employ, unlessotherwise indicated, conventional techniques of drug formulation,particularly topical and transdermal drug formulation, which are withinthe skill of the art. Such techniques are fully explained in theliterature. See Remington: The Science and Practice of Pharmacy, citedsupra, as well as Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 10^(th) Ed. (2001). Techniques that can be used for thepreparation of transdermal patches and the analysis thereof are furtherdescribed by U.S. Patent Publication No. 2012/0220962.

Definitions

The following definitions are included to provide a clear and consistentunderstanding of the specification and claims. As used herein, therecited terms have the following meanings. All other terms and phrasesused in this specification have their ordinary meanings as one of skillin the art would understand. Such ordinary meanings may be obtained byreference to technical dictionaries, such as Hawley's Condensed ChemicalDictionary 14^(th) Edition, by R. J. Lewis, John Wiley & Sons, New York,N.Y., 2001.

References in the specification to “one embodiment”, “an embodiment”,etc., indicate that the embodiment described may include a particularaspect, feature, structure, moiety, or characteristic, but not everyembodiment necessarily includes that aspect, feature, structure, moiety,or characteristic. Moreover, such phrases may, but do not necessarily,refer to the same embodiment referred to in other portions of thespecification. Further, when a particular aspect, feature, structure,moiety, or characteristic is described in connection with an embodiment,it is within the knowledge of one skilled in the art to affect orconnect such aspect, feature, structure, moiety, or characteristic withother embodiments, whether or not explicitly described.

The singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, a referenceto “a compound” includes a plurality of such compounds, so that acompound X includes a plurality of compounds X. It is further noted thatthe claims may be drafted to exclude any optional element. As such, thisstatement is intended to serve as antecedent basis for the use ofexclusive terminology, such as “solely,” “only,” and the like, inconnection with any element described herein, and/or the recitation ofclaim elements or use of “negative” limitations.

The term “and/or” means any one of the items, any combination of theitems, or all of the items with which this term is associated. Thephrases “one or more” and “at least one” are readily understood by oneof skill in the art, particularly when read in context of its usage. Forexample, the phrase can mean one, two, three, four, five, six, ten, 100,or any upper limit approximately 10, 100, or 1000 times higher than arecited lower limit.

The term “about” can refer to a variation of ±5%, ±10%, ±20%, or ±25% ofthe value specified. For example, “about 50” percent can in someembodiments carry a variation from 45 to 55 percent. For integer ranges,the term “about” can include one or two integers greater than and/orless than a recited integer at each end of the range. Unless indicatedotherwise herein, the term “about” is intended to include values, e.g.,weight percentages, proximate to the recited range that are equivalentin terms of the functionality of the individual ingredient, thecomposition, or the embodiment. The term about can also modify theend-points of a recited range as discuss above in this paragraph.

As will be understood by the skilled artisan, all numbers, includingthose expressing quantities of ingredients, properties such as molecularweight, reaction conditions, and so forth, are approximations and areunderstood as being optionally modified in all instances by the term“about.” These values can vary depending upon the desired propertiessought to be obtained by those skilled in the art utilizing theteachings of the descriptions herein. It is also understood that suchvalues inherently contain variability necessarily resulting from thestandard deviations found in their respective testing measurements.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges recited herein also encompass any and all possible sub-ranges andcombinations of sub-ranges thereof, as well as the individual valuesmaking up the range, particularly integer values. A recited range (e.g.,weight percentages or carbon groups) includes each specific value,integer, decimal, or identity within the range. Any listed range can beeasily recognized as sufficiently describing and enabling the same rangebeing broken down into at least equal halves, thirds, quarters, fifths,or tenths. As a non-limiting example, each range discussed herein can bereadily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art, all languagesuch as “up to”, “at least”, “greater than”, “less than”, “more than”,“or more”, and the like, include the number recited and such terms referto ranges that can be subsequently broken down into sub-ranges asdiscussed above. In the same manner, all ratios recited herein alsoinclude all sub-ratios falling within the broader ratio. Accordingly,specific values recited for radicals, substituents, and ranges, are forillustration only; they do not exclude other defined values or othervalues within defined ranges for radicals and substituents.

One skilled in the art will also readily recognize that where membersare grouped together in a common manner, such as in a Markush group, theinvention encompasses not only the entire group listed as a whole, buteach member of the group individually and all possible subgroups of themain group. Additionally, for all purposes, the invention encompassesnot only the main group, but also the main group absent one or more ofthe group members. The invention therefore envisages the explicitexclusion of any one or more of members of a recited group. Accordingly,provisos may apply to any of the disclosed categories or embodimentswhereby any one or more of the recited elements, species, orembodiments, may be excluded from such categories or embodiments, forexample, for use in an explicit negative limitation.

The term “contacting” refers to the act of touching, making contact, orof bringing to immediate or close proximity, including at the cellularor molecular level, for example, to bring about a physiologicalreaction, a chemical reaction, or a physical change, e.g., in asolution, in a reaction mixture, in vitro, or in vivo.

An “effective amount” refers to an amount effective to treat a disease,disorder, and/or condition, or to bring about a recited effect. Forexample, an effective amount can be an amount effective to reduce theprogression or severity of the condition or symptoms being treated.Determination of a therapeutically effective amount is well within thecapacity of persons skilled in the art. The term “effective amount” isintended to include an amount of a compound described herein, or anamount of a combination of compounds described herein, e.g., that iseffective to treat or prevent a disease or disorder, or to treat thesymptoms of the disease or disorder, in a host. Thus, an “effectiveamount” generally means an amount that provides the desired effect.

The terms “treating”, “treat” and “treatment” include (i) preventing adisease, pathologic or medical condition from occurring (e.g.,prophylaxis); (ii) inhibiting the disease, pathologic or medicalcondition or arresting its development; (iii) relieving the disease,pathologic or medical condition; and/or (iv) diminishing symptomsassociated with the disease, pathologic or medical condition. Thus, theterms “treat”, “treatment”, and “treating” can extend to prophylaxis andcan include prevent, prevention, preventing, lowering, stopping orreversing the progression or severity of the condition or symptoms beingtreated. As such, the term “treatment” can include medical, therapeutic,and/or prophylactic administration, as appropriate.

The terms “inhibit”, “inhibiting”, and “inhibition” refer to theslowing, halting, or reversing the growth or progression of a disease,infection, condition, or group of cells. The inhibition can be greaterthan about 20%, 40%, 60%, 80%, 90%, 95%, or 99%, for example, comparedto the growth or progression that occurs in the absence of the treatmentor contacting.

“Body surface” is used to refer to skin or mucosal tissue.

“Carriers” or “vehicles” as used herein refer to carrier materialssuitable for transdermal or topical drug administration. Carriers andvehicles useful herein include any such materials known in the art,which are nontoxic and do not interact with other components of thecomposition in a deleterious manner.

“Penetration enhancement” or “permeation enhancement” as used hereinrelates to an increase in the permeability of the skin or mucosal tissueto the selected pharmacologically active agent, i.e., so that the rateat which the agent permeates therethrough (i.e., the “flux” of the agentthrough the body surface) is increased relative to the rate that wouldbe obtained in the absence of permeation enhancer. The enhancedpermeation effected through the use of such enhancers can be observed bymeasuring the rate of diffusion of drug through animal or human skinusing, for example a Franz diffusion apparatus as known in the art andas employed in the Examples herein.

“Predetermined area” of skin or mucosal tissue refers to the area ofskin or mucosal tissue through which a drug-enhancer formulation isdelivered, and is a defined area of intact unbroken living skin ormucosal tissue. That area will usually be in the range of about 5-200cm², more usually in the range of about 5-100 cm², preferably in therange of about 20-60 cm². However, it will be appreciated by thoseskilled in the art of drug delivery that the area of skin or mucosaltissue through which drug is administered may vary significantly,depending on patch configuration, dose, and the like.

“Topical administration” is used in its conventional sense to meandelivery of a topical drug or pharmacologically active agent to the skinor mucosa, as in, for example, the treatment of various skin disorders.Topical administration, in contrast to transdermal administration,provides a local rather than a systemic effect. However, unlessotherwise stated or implied, the terms “topical drug administration” and“transdermal drug administration” are used interchangeably.

“Transdermal” drug delivery is meant administration of a drug to theskin surface of an individual so that the drug passes through the skintissue and into the individual's blood stream, thereby providing asystemic effect. The term “transdermal” is intended to include“transmucosal” drug administration, i.e., administration of a drug tothe mucosal (e.g., sublingual, buccal, vaginal, rectal) surface of anindividual so that the drug passes through the mucosal tissue and intothe individual's blood stream.

Drug Reservoir Components and Variations

The components of the drug reservoir can be aqueous or non-aqueous. Thereservoir can include a topical formulation such as a gel, ointment,lotion, or other topical formulation, typically in combination with anadhesive. Accordingly, while the method of delivery of the active agentmay vary, the method will typically involve application of a formulationor drug delivery system containing a pharmaceutically acceptable carrierto a predetermined area of the skin or other tissue for a period of timesufficient to provide the desired local or systemic effect. The methodmay involve direct application of the composition as an ointment, gel,cream, or the like, or may involve use of a drug delivery device such asa patch. In either case, water can be present in order for ions to beprovided and thus enhance the flux of the active agent through thepatient's body surface. Thus, such a formulation or drug reservoir maybe aqueous, i.e., contain water, or may be nonaqueous and used incombination with an occlusive backing layer so that moisture evaporatingfrom the body surface is maintained within the formulation ortransdermal system during drug administration. In some cases, however,e.g., with an occlusive gel, a nonaqueous formulation may be used withor without an occlusive backing layer.

Suitable formulations include ointments, creams, gels, lotions,solutions, pastes, and the like. Ointments, as is well known in the artof pharmaceutical formulation, are semisolid preparations that aretypically based on petrolatum or other petroleum derivatives. Thespecific ointment foundation to be used, as will be appreciated by thoseskilled in the art, is one that will provide for optimum drug delivery,and, preferably, will provide for other desired characteristics as well,e.g., emolliency or the like. As with other carriers or vehicles, theointment foundation should be inert, stable, nonirritating andnonsensitizing. As explained in Remington: The Science and Practice ofPharmacy, 22^(th) edition (Lippincott Williams & Wilkins, 2000),ointment foundations may be grouped in four classes: oleaginous,emulsifiable, emulsion, and water-soluble. Oleaginous ointmentfoundations include, for example, vegetable oils, fats obtained fromanimals, and semisolid hydrocarbons obtained from petroleum.Emulsifiable ointment foundations, also known as absorbent ointmentfoundations, contain little or no water and include, for example,hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum.Emulsion ointment foundations are either water-in-oil (W/O) emulsions oroil-in-water (O/W) emulsions, and include, for example, cetyl alcohol,glyceryl monostearate, lanolin and stearic acid. Preferred water-solubleointment foundations are prepared from polyethylene glycols of varyingmolecular weight.

Creams, as also well known in the art, are viscous liquids or semisolidemulsions, either oil-in-water or water-in-oil. Cream foundations arewater-washable, and contain an oil phase, an emulsifier and an aqueousphase. The oil phase, also called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. The aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant.

As will be appreciated by those working in the field of pharmaceuticalformulation, gels are semisolid, suspension-type systems. Single-phasegels contain organic macromolecules distributed substantially uniformlythroughout the carrier liquid, which is typically aqueous, but also maycontain an alcohol and, optionally, an oil. Preferred organicmacromolecules, i.e., gelling agents, are crosslinked acrylic acidpolymers such as the “carbomer” family of polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under theCarbopol® trademark. Also preferred are hydrophilic polymers such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers andpolyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methyl cellulose; gums such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixingor stirring, or combinations thereof.

Lotions, which are preferred for delivery of cosmetic agents, arepreparations to be applied to the skin surface without friction, and aretypically liquid or semiliquid preparations in which solid particles,including the active agent, are present in a water or alcohol base.Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. Lotions are preferred formulations herein for treating large bodyareas, because of the ease of applying a more fluid composition. It isgenerally necessary that the insoluble matter in a lotion be finelydivided. Lotions will typically contain suspending agents to producebetter dispersions as well as compounds useful for localizing andholding the active agent in contact with the skin, e.g.,methylcellulose, sodium carboxymethyl-cellulose, or the like.

Solutions are homogeneous mixtures prepared by dissolving one or morechemical substances (solute) in another liquid such that the moleculesof the dissolved substance are dispersed among those of the solvent. Thesolution may contain other pharmaceutically acceptable chemicals tobuffer, stabilize or preserve the solute. Commonly used examples ofsolvents used in preparing solutions are ethanol, water, propyleneglycol or any other pharmaceutically acceptable vehicle.

Pastes are semisolid dosage forms in which the active agent is suspendedin a suitable foundation. Depending on the nature of the foundation,pastes are divided between fatty pastes or those made from single-phase,aqueous gels. The foundation in a fatty paste is generally petrolatum orhydrophilic petrolatum or the like. The pastes made from single-phaseaqueous gels generally incorporate carboxymethylcellulose or the like asthe foundation.

Formulations may also be prepared with liposomes, micelles, andmicrospheres. Liposomes are microscopic vesicles having a lipid wallcomprising a lipid bilayer, and can be used as drug delivery systemsherein as well. Generally, liposome formulations are preferred forpoorly soluble or insoluble pharmaceutical agents. Liposomalpreparations for use in the instant invention include cationic(positively charged), anionic (negatively charged) and neutralpreparations. Cationic liposomes are readily available. For example,N-[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium liposomes areavailable under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Anionic and neutral liposomes are readily available as well,e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can be easilyprepared using readily available materials. Such materials includephosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline, dioleoylphosphatidyl glycerol,dioleoylphoshatidyl ethanolamine, among others. These materials can alsobe mixed with N-[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (DOTMA)in appropriate ratios. Methods for making liposomes using thesematerials are well known in the art.

Micelles are known in the art and are comprised of surfactant moleculesarranged so that their polar headgroups form an outer spherical shell,while the hydrophobic, hydrocarbon chains are oriented towards thecenter of the sphere, forming a core. Micelles form in an aqueoussolution containing surfactant at a high enough concentration so thatmicelles naturally result. Surfactants useful for forming micellesinclude, but are not limited to, potassium laurate, sodium octanesulfonate, sodium decane sulfonate, sodium dodecane sulfonate, sodiumlauryl sulfate, docusate sodium, decyltrimethylammonium bromide,dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,tetradecyltrimethyl-ammonium chloride, dodecylammonium chloride,polyoxyl 8 dodecyl ether, polyoxyl 12 dodecyl ether, nonoxynol 10 andnonoxynol 30. Micelle formulations can be used in conjunction with thepresent invention either by incorporation into the reservoir of atopical or transdermal delivery system, or into a formulation to beapplied to the body surface.

Microspheres, similarly, may be incorporated into the presentformulations and drug delivery systems. Like liposomes and micelles,microspheres essentially encapsulate a drug or drug-containingformulation. They are generally, although not necessarily, formed fromlipids, preferably charged lipids such as phospholipids. Preparation oflipidic microspheres is well known in the art and described in thepertinent texts and literature.

Various additives, known to those skilled in the art, may be included inthe topical formulations. For example, solvents, including relativelysmall amounts of alcohol, may be used to solubilize certain drugsubstances. Other optional additives include opacifiers, antioxidants,fragrance, colorant, gelling agents, thickening agents, stabilizers,surfactants and the like. Other agents may also be added, such asantimicrobial agents, to prevent spoilage upon storage, i.e., to inhibitgrowth of microbes such as yeasts and molds. Suitable antimicrobialagents are typically selected from the group consisting of the methyland propyl esters of p-hydroxybenzoic acid (i.e., methyl and propylparaben), sodium benzoate, sorbic acid, imidurea, and combinationsthereof.

For those drugs having an unusually low rate of permeation through theskin or mucosal tissue, it may be desirable to include a secondpermeation enhancer in the formulation in addition to the inorganic ororganic base enhancer, although in a preferred embodiment the baseenhancer is administered without any other permeation enhancers. Anyother enhancers should, like the base enhancer, minimize the possibilityof skin damage, irritation, and systemic toxicity. Examples of classesof suitable secondary enhancers (or “co-enhancers”) include, but are notlimited to, fatty acids, both saturated and unsaturated; fatty alcohols;bile acids; nonionic surfactants, including esters of fatty acids, fatty(long-chain alkyl or alkenyl) esters of monohydric alcohols, diols, andpolyols, diols and polyols that are both esterified with a fatty acidand substituted with a polyoxyalkylene, polyoxyalkylene fatty acidesters, polyoxyalkylene fatty ethers, polyoxyalkylene fatty ethers, andpolyglyceryl fatty acid esters; amines; amides;N-alkyl-azacycloalkanones and N-alkyl-azacycloalkenones; hydrocarbonsolvents; terpenes; lower alkyl esters; cyclodextrin enhancers;nitrogen-containing heterocycles; sulfoxides; and urea and itsderivatives.

Specific examples of suitable co-enhancers include ethers such asdiethylene glycol monoethyl ether (available commercially as Transcutol®solvent, Gattefosse SA) and diethylene glycol monomethyl ether;surfactants such as sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231,182, 184), Tween (20, 40, 60, 80) and lecithin; alcohols such asethanol, propanol, octanol, benzyl alcohol, and the like; fatty acidssuch as lauric acid, oleic acid and valeric acid; fatty acid esters suchas isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyloleate; polyols and esters thereof such as polyethylene glycol, andpolyethylene glycol monolaurate; amides and other nitrogenous compoundssuch as urea, dimethylacetamide, dimethylformamide, 2-pyrrolidone,1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; and organic acids, particularlycitric acid and succinic acid. Azone® and sulfoxides such asdimethylsulfoxide and decylmethylsulfoxide may also be used, but areless preferred. Percutaneous Penetration Enhancers, eds. Smith et al.(CRC Press, 1995) provides an excellent overview of the field andfurther information concerning possible secondary enhancers for use inconjunction with the present invention.

The formulation may also contain irritation-mitigating additives tominimize or eliminate the possibility of skin irritation or skin damageresulting from the drug, the base enhancer, or other components of theformulation. Suitable irritation-mitigating additives include, forexample: α-tocopherol; monoamine oxidase inhibitors, particularly phenylalcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acids andsalicylates; ascorbic acids and ascorbates; ionophores such as monensin;amphiphilic amines; ammonium chloride; N-acetylcysteine; cis-urocanicacid; capsaicin; and chloroquine. The irritant-mitigating additive, ifpresent, may be incorporated into the formulation at a concentrationeffective to mitigate irritation or skin damage, typically representingnot more than about 20 wt %, more typically not more than about 5 wt %,of the formulation.

The concentration of the active agent in the formulation (e.g., vitaminD₃) will typically depend upon a variety of factors, including thedisease or condition to be treated, the nature and activity of theactive agent, the desired effect, possible adverse reactions, theability and speed of the active agent to reach its intended target, andother factors within the particular knowledge of the patient andphysician. Preferred formulations will typically contain on the order ofabout 0.5-50 wt %, preferably about 2-30 wt %, active agent (i.e.,vitamin D₃), or about 5-30 wt %, active agent.

In some embodiments, formulation can further include one to threeadditional vitamin and/or mineral components. One optional component isvitamin K₂, which can be present at about 50 μg to about 250 μg perdose, or about 100 μg to about 200 μg per dose. The formulations canalso include about 50 mg to about 500 mg of magnesium, about 200 mg toabout 300 mg of magnesium, or about 250 mg of magnesium.

Pharmaceutical Formulations

The compounds described herein can be used to prepare therapeuticpharmaceutical compositions, for example, by combining the compoundswith a pharmaceutically acceptable diluent, excipient, or carrier. Thecompounds may be added to a carrier in the form of a salt or solvate.For example, in cases where compounds are sufficiently basic or acidicto form stable nontoxic acid or base salts, administration of thecompounds as salts may be appropriate. Examples of pharmaceuticallyacceptable salts are organic acid addition salts formed with acids thatform a physiological acceptable anion, for example, tosylate,methanesulfonate, acetate, citrate, malonate, tartrate, succinate,benzoate, ascorbate, α-ketoglutarate, and β-glycerophosphate. Suitableinorganic salts may also be formed, including hydrochloride, halide,sulfate, nitrate, bicarbonate, and carbonate salts.

Pharmaceutically acceptable salts may be obtained using standardprocedures well known in the art, for example by reacting a sufficientlybasic compound such as an amine with a suitable acid to provide aphysiologically acceptable ionic compound. Alkali metal (for example,sodium, potassium or lithium) or alkaline earth metal (for example,calcium) salts of carboxylic acids can also be prepared by analogousmethods.

The compounds of the formulas described herein can be formulated aspharmaceutical compositions and administered to a mammalian host, suchas a human patient, in a variety of forms. The forms can be specificallyadapted to a chosen route of administration, e.g., topical, transdermal,or transmucosal routes.

The compounds described herein may be systemically administered incombination with a pharmaceutically acceptable vehicle, such as an inertdiluent. The compositions and preparations typically contain at least0.1% of active compound (i.e., a fat soluble vitamin such as vitamin D).The percentage of the compositions and preparations can vary and mayconveniently be from about 0.5% to about 60%, about 1% to about 25%, orabout 2% to about 10%, of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositionscan be such that an effective dosage level can be obtained.

Solutions of the active compound or its salts can be prepared in wateror an organic solvent, optionally mixed with a nontoxic surfactant.Dispersions can be prepared in glycerol, liquid polyethylene glycols,triacetin, or mixtures thereof, or in a pharmaceutically acceptable oil.Solutions or dispersions can also be prepared using triglycerides suchas triglycerides having a combination of caprylic and capric fattyacids, commercially available as Labrafac Lipophile WL1349 oil. Underordinary conditions of storage and use, preparations may contain apreservative to prevent the growth of microorganisms.

For topical administration, compounds may be applied in pure form, e.g.,when they are liquids. However, it will generally be desirable toadminister the active agent to the skin as a composition or formulation,for example, in combination with a dermatologically acceptable carrier,which may be a solid, a liquid, a gel, or the like.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, dimethyl sulfoxide (DMSO), alcohols, glycols, orwater-alcohol/glycol blends, in which a compound can be dissolved ordispersed at effective levels, optionally with the aid of non-toxicsurfactants. Adjuvants such as fragrances and additional antimicrobialagents can be added to optimize the properties for a given use. Theresultant liquid compositions can be applied from absorbent pads, usedto impregnate bandages and other dressings, or sprayed onto the affectedarea using a pump-type or aerosol sprayer, and optionally be coveredwith an occlusive bandage to enhance absorption.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses, or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Examples of dermatological compositions for delivering active agents tothe skin are known to the art; for example, see U.S. Pat. No. 4,992,478(Geria), U.S. Pat. No. 4,820,508 (Wortzman), U.S. Pat. No. 4,608,392(Jacquet et al.), and U.S. Pat. No. 4,559,157 (Smith et al.). Suchdermatological compositions can be used in combinations with thecompounds described herein where an ingredient of such compositions canoptionally be replaced by a compound described herein, or a compounddescribed herein can be added to the composition.

Useful dosages of the actives described herein can be determined bycomparing their in vitro activity, and in vivo activity in animalmodels. Methods for the extrapolation of effective dosages in mice, andother animals, to humans are known to the art; for example, see U.S.Pat. No. 4,938,949 (Borch et al.). The amount of a compound, or anactive salt or derivative thereof, required for use in treatment willvary not only with the particular compound or salt selected but alsowith the route of administration, the nature of the condition beingtreated, and the age and condition of the patient, and will beultimately at the discretion of an attendant physician or clinician.

The following Examples are intended to illustrate the above inventionand should not be construed as to narrow its scope. One skilled in theart will readily recognize that the Examples suggest many other ways inwhich the invention could be practiced. It should be understood thatnumerous variations and modifications may be made while remaining withinthe scope of the invention.

EXAMPLES Example 1. Vitamin D₃ Transdermal Delivery

Franz cell permeation of vitamin D₃ was performed to evaluate variousformulations lacking adhesives and the results were analyzed as shown inFIGS. 1 and 2 (transdermal permeation of cholecalciferol through theFranz cells for the P39 formulation (lacking PIB and NaOH) and the Test1 formulation).

Sample analysis: Permeation samples were analyzed using HPLC with UVdetection at 265 nm. A QC standard was prepared using cholecalciferoldissolved in acetonitrile and diluting the same with permeation receiverbuffer to obtain a working standard containing about 0.05 mg/mL ofcholecalciferol. The second QC standard was prepared as control. Thestandard was injected was injected five times and the % RSD of thesefive injections were found to be 0.07. The QC control solution wasinjected in replicate and the recovery of cholecalciferol was 104.3%when tested against the standard. This comprised the HPLC systemsuitability before the analysis of the experimental samples. Furtherduring the analysis bracketing standards were injected and theirrecoveries were calculated against the average of initial fiveinjections to calculate HPLC system drift during the analysis.

Favorable stability results were discovered for P39 formulations thatdid not contain sodium hydroxide. Accordingly, experiments wereperformed to confirm that the modified formulations indeed transfervitamin D through skin. Formulation P39A contains the same components asP39 except that it excludes sodium hydroxide, PIB adhesives, and PVP.Formulation P39B contains the same components as P39 except that itexcludes sodium hydroxide and PIB adhesives.

Composition of P39A and B:

P39 P39A P39B Components: Quantity (g) Quantity (g) Quantity (g)Cholecalciferol 0.2 0.2 0.2 Diethylene glycol mono ethyl 1.0 1.0 1.0ether Sodium lauroyl sarcosinate 0.1 0.1 0.1 Poly vinyl pyrrolidine(PVP) 0.7 0 0.7 DURO-TAK 87-6908 (PIB) 15.0 0 0 Polyisobutylene 926 0.50 0 Sodium hydroxide (50% aq.) 0.3 0 0 Distilled water 1.0 1.0 1.0 Total18.8 2.3 3.0 D3 Concentration approx. 0.01 g/mL 0.087 g/mL 0.067 g/mLComposition of Test 1:

Ingredients: Quantity (g) Cholecalciferol 0.2 Ethyl alcohol 0.5Transcutol 1.0 Total 1.7 D3 Concentration approx. 0.13 g/mL

TABLE A Transdermal Delivery of Cholecalciferol: Results for Permeationfrom Formulations without Adhesive (FIGS. 1 and 2) Volume of ReceiverCross Sectional Area (cm2) = Cum. Solution Sampled 1.13 Amount Volume ofReceiver (mL) = (mL) = 1 Cumulative Permeated/ 7.50 Time-Cholecalciferol Amount Unit Area S No. Study: point (h) found (ug) Perm.(ug) (ug/cm2) P39 no adhesive, no NaOH 1 Permeation cell-1 5 h 5 6.106.10 5.40 2 Permeation cell-1 10 h 10 5.17 5.98 5.30 3 Permeation cell-124 h 24 4.85 6.46 5.72 4 Permeation cell-1 36 h 36 4.08 6.55 5.80 5Permeation cell-1 48 h 48 4.05 7.39 6.54 P39 with PVP, no adhesive, noNaOH 1 Permeation cell-2 5 h 5 9.15 9.15 8.10 2 Permeation cell-2 10 h10 8.00 9.22 8.16 3 Permeation cell-2 24 h 24 6.98 9.43 8.34 4Permeation cell-2 36 h 36 6.08 9.79 8.66 5 Permeation cell-2 48 h 485.50 10.51 9.30 Test 1, no adhesive 1 Permeation cell-3 5 h 5 72.8372.83 64.45 2 Permeation cell-3 10 h 10 60.15 69.86 61.82 3 Permeationcell-3 24 h 24 52.56 71.59 63.35 4 Permeation cell-3 36 h 36 44.12 72.6964.33 15% DMSO (Control) 1 Permeation cell-4 5 h 5 56.25 56.25 49.78 2Permeation cell-4 10 h 10 48.73 56.23 49.76 3 Permeation cell-4 24 h 2442.46 57.46 50.85 4 Permeation cell-4 36 h 36 35.91 58.56 51.83 5Permeation cell-4 48 h 48 31.29 61.76 54.66 15% Ethanol (Control) 1Permeation cell-5 5 h 5 2.87 2.87 2.54 2 Permeation cell-5 10 h 10 2.482.86 2.53 3 Permeation cell-5 24 h 24 2.10 2.86 2.53 4 Permeation cell-536 h 36 1.76 2.91 2.57 5 Permeation cell-5 48 h 48 1.58 3.11 2.76

Franz cell permeation of vitamin D₃ was then performed to evaluatevarious formulations that included adhesives (Patch #13 and Patch #14).The results were analyzed and the data is shown in FIGS. 3 and 4 .

Patch#13 Lot#FNEK-20150724-1, IDE Ingredients: Quantity (g)Cholecalciferol 0.2 Labrafac Lipophile WL1349 (oil) 0.6 Isosorbidedimethyl ether 0.3 DURO-TAK 87-6908 (PIB) 9.0 Total 10.1

Patch#14 Lot#FNEK-20150724-2, IPL Ingredients: Quantity (g)Cholecalciferol 0.2 Labrafac Lipophile WL1349 (oil) 0.6 Isopropyllaurate 0.3 DURO-TAK 87-6908 (PIB) 9.0 Total 10.1Procedure for Preparation of Patch #13 and Patch #14:

Vitamin D₃ (cholecalciferol) was weighed and added to a pre-weighedquantity of labrafac lipophile WL1349 (caprylic/capric triglyceride oilmixture) and mixed for about half an hour. The required quantity ofisosorbide dimethyl ether (to prepare Patch #13) or isopropyl laurate(to prepare Patch #14) was added to the mixture and mixing was continueduntil a homogenous blend was obtained, at which point thecholecalciferol was nearly fully solvated. The desired quantity of PIBwas added to the mixture and the blend was mixed overnight by tumblingaction on a rotor. The mixture was then coated to 15 mil thickness ontoa Scotchpak 1022 release liner and placed in a circulating air oven at55° C. for 15 minutes. The coated release liner was then removed fromthe oven and was allowed to cool to room temperature (˜22° C.). Abacking liner (Scotchpak™ 9733 Backing Polyester Film Laminate) wasplaced on the coated release liner, with the EVA side facing up. Thepatches were then pressed by a roller to remove air gaps and to provideefficient bonding with the backing, to provide the final transdermalpatch.

Finally, given the successful transdermal delivery of vitamin D via theformulations of Patch #13 and Patch #14, commercially available patcheswere then evaluated for their transdermal delivery of vitamin D asdetermined by Franz Cell analysis. Using the same methods describedabove, the commercial products Respro Laboratories Vitamin D Patch(280,000 I.U.), Patch MD Vitamin D3 Topical Patch (5,000 I.U.), andLiving Nutritionals Vitamin D3 Sunshine Patch (5,000 I.U.) wereevaluated. As shown in FIG. 5 , while each of these products contain atleast 5,000 I.U. of vitamin D₃, none of them actually transdermallydelivered the vitamin D₃ through the cadaver skill in the Franz Cellanalysis. Furthermore, only the Respro Laboratories Vitamin D Patch(280,000 I.U.) even released any detectable amounts of vitamin D₃ whenthe experiments were run without cadaver skin, although the ResproLaboratories Vitamin D Patch release less vitamin D₃ than Patch #13 andPatch #14.

While specific embodiments have been described above with reference tothe disclosed embodiments and examples, such embodiments are onlyillustrative and do not limit the scope of the invention. Changes andmodifications can be made in accordance with ordinary skill in the artwithout departing from the invention in its broader aspects as definedin the following claims.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Nolimitations inconsistent with this disclosure are to be understoodtherefrom. The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, it should beunderstood that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

What is claimed is:
 1. A transdermal patch for the transdermaladministration of cholecalciferol comprising: (a) a backing layer thatserves as the outer surface of the patch during use; (b) an adhesivedrug reservoir layer for affixing the patch to human skin; and (c) arelease liner, which upon removal exposes the adhesive drug reservoirlayer; wherein the adhesive drug reservoir layer consists of about 1 toabout 10 wt % cholecalciferol, a polymeric adhesive, an organic solvent,and a permeation enhancer; the adhesive drug reservoir layer comprisesabout 1-15 wt. % organic solvent; and the organic solvent comprisesisosorbide dimethyl ether or isopropyl laurate.
 2. The transdermal patchof claim 1 wherein the adhesive is a polyisobutylene adhesive, asilicone adhesive; or an acrylate adhesive.
 3. The transdermal patch ofclaim 1 wherein the adhesive drug reservoir layer comprises about 60-90wt. % polymeric adhesive, and the adhesive drug reservoir layercomprises about 1-15 wt. % permeation enhancer.
 4. The transdermal patchof claim 1 wherein the adhesive is an acrylate or polyisobutyleneadhesive, the organic solvent comprises a triglyceride, and thepermeation enhancer is transcutol.
 5. The transdermal patch of claim 1wherein the adhesive drug reservoir layer does not contain water.
 6. Thetransdermal patch of claim 1 wherein the surface area of the adhesivedrug reservoir layer of the patch is about 30 cm² to about 50 cm². 7.The transdermal patch of claim 6 wherein the patch is formulated todeliver greater than 2,000 μg of cholecalciferol through 40 cm² ofintact unbroken living skin in within 5 hours.
 8. The transdermal patchof claim 6 wherein the patch is formulated to deliver greater than20,000 μg of cholecalciferol through 40 cm² of intact unbroken livingskin in within 24 hours.
 9. The transdermal patch of claim 6 wherein thepatch is formulated to contain about 4,000-5,000 I.U. ofcholecalciferol.
 10. A transdermal patch for the transdermaladministration of cholecalciferol consisting of: (a) a backing layerthat serves as the outer surface of the patch during use; (b) anadhesive drug reservoir layer for affixing the patch to human skin; and(c) a release liner, which upon removal exposes the adhesive drugreservoir layer; wherein the adhesive drug reservoir layer consists of1-10 wt. % of cholecalciferol, 60-90 wt. % of a polymeric adhesive, 1-15wt. % of an organic solvent, and 1-15 wt. % of transcutol; and whereinthe organic solvent comprises isosorbide dimethyl ether or isopropyllaurate.
 11. The transdermal patch of claim 10 wherein the adhesive drugreservoir layer consists of 3 wt. % of cholecalciferol, 80-85 wt. % of apolymeric adhesive, the organic solvent, and 5-10 wt. % of transcutol.12. A method for the transdermal delivery of vitamin D comprisingremoving the release liner of the transdermal patch of claim 10 andapplying the transdermal patch to intact unbroken living skin of a humansubject, wherein the transdermal patch delivers greater than 0.75 μg/cm²of cholecalciferol to the subject within 5 hours.
 13. The method ofclaim 12 wherein the transdermal patch is applied to a subject having a25-hydroxyvitamin D₃ (calcifediol) blood serum level of less than 30ng/mL.
 14. The method of claim 13 wherein the transdermal patch isapplied to a subject having a 25-hydroxyvitamin D₃ (calcifediol) bloodserum level of about 1 ng/mL to about 25 ng/mL.
 15. The method of claim14 wherein the 25-hydroxyvitamin D₃ (calcifediol) blood serum level ofthe subject increases to greater than 30 ng/mL within 5 hours.
 16. Themethod of claim 12 wherein the transdermal patch is applied to thesubject once per day for at least 5 days.
 17. The method of claim 15wherein the human subject has a 25-hydroxyvitamin D₃ (calcifediol) bloodserum level of less than 20 ng/mL.
 18. The method of claim 17 whereinthe human subject has cystic fibrosis, is older than 65 years of age, orhas undergone bariatric surgery.
 19. A method of increasing the25-hydroxyvitamin D₃ (calcifediol) blood serum level of a human subjectthat has a vitamin D malabsorption condition comprising removing therelease liner of the transdermal patch of claim 1 and applying thetransdermal patch to intact unbroken living skin of the human subject,wherein the 25-hydroxyvitamin D₃ (calcifediol) blood serum level of thesubject increases to greater than 20 ng/mL within 24 hours.
 20. Themethod of claim 19 wherein the human subject that has a vitamin Dmalabsorption condition is a subject that has been diagnosed with cysticfibrosis.
 21. A transdermal patch for the transdermal administration ofcholecalciferol consisting of: (a) a backing layer that serves as theouter surface of the patch during use; (b) an adhesive drug reservoirlayer for affixing the patch to human skin; and (c) a release liner,which upon removal exposes the adhesive drug reservoir layer; whereinthe adhesive drug reservoir layer consists of 1-10 wt. % ofcholecalciferol, 80-85 wt. % of a polymeric adhesive, 1-15 wt. % of anorganic solvent, and 1-15 wt. % of transcutol; wherein the organicsolvent comprises isosorbide dimethyl ether or isopropyl laurate; andwherein the patch is formulated to deliver greater than 2,000 μg ofcholecalciferol through 40 cm² of intact unbroken skin in within 5hours; and wherein the organic solvent comprises isosorbide dimethylether or isopropyl laurate.